The role and therapeutic potential of succinate and succinylation in cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of global mortality and disease burden, with pathogenesis involving metabolic remodelling and inflammatory responses. Metabolic remodelling is also increasingly regarded as a key factor in the pathogenesis of CVDs, leading to the abnormal accumulation of metabolic intermediates. Current research has shown that succinate, an intermediate product of the tricarboxylic acid cycle (TCA), significantly accumulates in CVDs, promoting the occurrence of disease. In recent years, the role of epigenetics in CVDs has received increasing attention. Compared with its modification, succinylation modification directly links metabolism and epigenetics. Therefore, in CVDs where metabolic remodelling is a key factor, succinylation modification may play a crucial role. This article describes the role of succinate and succinylation modifications in CVDs. For example, in ischaemia‒reperfusion injury (IRI), the abnormal accumulation of succinate during ischaemia and the oxidation of succinate by succinylation dehydrogenase (SDH) during reperfusion lead to the production of large amounts of reactive oxygen species (ROS), and the succinylation modification of carnitine palmitoyltransferase 2 (CPT2) at lysine 424 increases the lipotoxicity to diabetic hearts. In addition, given the significant role of succinate and succinylation modifications in the cardiovascular system, we focused on therapeutic strategies targeting succinate and succinylation modifications, including inhibitors of SDH, inhibitors of succinate receptor 1 (SUCNR1), and activators of sirtuin 5 (SIRT5), providing new insights for CVD intervention.